Coating comprising a terpolymer comprising caprolactone and glycolide

ABSTRACT

The present invention provides a coating comprising a reservoir layer comprising a terpolymer comprising caprolactone and glycolide and a primer layer comprising an amorphous polymer on an implantable device and methods of making and using the same.

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation of U.S. application Ser. No. 12/466,317, filed onMay 14, 2009, which is a continuation-in-part application of U.S.application Ser. No. 12/124,991, filed on May 21, 2008, the teaching ofwhich is incorporated herein in its entirety by reference.

FIELD OF THE INVENTION

The present invention relates to a terpolymer for coating an implantabledevice.

BACKGROUND OF THE INVENTION

Percutaneous coronary intervention (PCI) is a procedure for treatingheart disease. A catheter assembly having a balloon portion isintroduced percutaneously into the cardiovascular system of a patientvia the brachial or femoral artery. The catheter assembly is advancedthrough the coronary vasculature until the balloon portion is positionedacross the occlusive lesion. Once in position across the lesion, theballoon is inflated to a predetermined size to radially compress theatherosclerotic plaque of the lesion to remodel the lumen wall. Theballoon is then deflated to a smaller profile to allow the catheter tobe withdrawn from the patient's vasculature.

Problems associated with the above procedure include formation ofintimal flaps or torn arterial linings which can collapse and occludethe blood conduit after the balloon is deflated. Moreover, thrombosisand restenosis of the artery may develop over several months after theprocedure, which may require another angioplasty procedure or a surgicalby-pass operation. To reduce the partial or total occlusion of theartery by the collapse of the arterial lining and to reduce the chanceof thrombosis or restenosis, a stent is implanted in the artery to keepthe artery open.

Drug delivery stents have reduced the incidence of in-stent restenosis(ISR) after PCI (see, e.g., Serruys, P. W., et al., J. Am. Coll.Cardiol. 39:393-399 (2002)), which has plagued interventional cardiologyfor more than a decade. However, a few challenges remain in the art ofdrug delivery stents. For example, compromised coating integrity when anamorphous bioabsorbable polymer is used for coating a stent, which canresult from the conditions of ethylene oxide (ETO) sterilization or fromthe conditions of crimping a stent onto the delivery balloon. Conditionssuch as elevated temperature, high relative humidity, and highconcentration of ETO in the ETO sterilization process can result inplasticization and adhesion of the coating to the balloon via polymerdeformation and flow. In a similar way a completely amorphousbioabsorbable polymer may flow when crimped at elevated temperatures onto the delivery balloon.

The embodiments of the present invention address the above-identifiedneeds and issues.

SUMMARY OF THE INVENTION

The present invention provides an implantable device. The implantabledevice comprises a coating comprising a layer comprising a terpolymer.The terpolymer comprises caprolactone, glycolide and a third monomere,which terpolymer has a molar composition where caprolactone is about 20%or higher, and glycolide is about 10% or higher. In some embodiments,the third monomer is a lactide, e.g., D,L-lactide, L-lactide, orracemic-D,L-lactide.

In some embodiments, optionally with one or any combination of featuresof the various embodiments above or below, the terpolymer has a glasstransition temperature (T_(g)) less than 37° C.

In some embodiments, optionally with one or any combination of featuresof the various embodiments above or below, the the coating maintains itsintegrity after ethylene oxide (ETO) sterilization or e-beam treatment.

In some embodiments, optionally with one or any combination of featuresof the various embodiments above or below, the coating can have variousthickness. In some embodiments, the coating has a thickness of about 5microns or less and a degradation or absorption rate that within aperiod of 6 months after deployment of the implantable device, thecoating has a mass loss of about 80% or more.

In some embodiments, optionally with one or any combination of featuresof the various embodiments above or below, the coating can comprises aprimer comprising a biodegradable amorphous polymer.

In some embodiments, optionally with one or any combination of featuresof the various embodiments above or below, the coating can furthercomprise a bioactive agent and provides a controlled release of thebioactive agent when the implantable device is deployed. Examples of thebioactive agent are paclitaxel, docetaxel, estradiol, 17-beta-estradiol,nitric oxide donors, super oxide dismutases, super oxide dismutasemimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),biolimus, tacrolimus, dexamethasone, dexamethasone derivatives,glucocorticoids, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), temsirolimus, deforolimus,γ-hiridun, clobetasol, pimecrolimus, imatinib mesylate, midostaurin,feno fibrate, prodrugs thereof, co-drugs thereof, and combinationsthereof.

In some embodiments, optionally with one or any combination of featuresof the various embodiments above or below, the coating a degradation orabsorption rate that within a period of about 100 days after deploymentof the implantable device, the coating has a mass loss of about 80% ormore. In some embodiments, the coating has a mass loss of about 100%within 100 days or 180 days after deployment of the implantable device.

In some embodiments, optionally with one or any combination of featuresof the various embodiments above or below, the implantable device is astent or a a bioabsorbable stent.

The present invention also provides a method of fabricating animplantable device. The method generally comprises forming a coating ofthe various embodiments described above or below.

The present invention also provides a method of treating, preventing, orameliorating a vascular medical condition. The method generallycomprises implanting in a patient an implantable device according to thevarious embodiments described above or below. Examples of the vascularmedical condition are restenosis, atherosclerosis, thrombosis,hemorrhage, vascular dissection or perforation, vascular aneurysm,vulnerable plaque, chronic total occlusion, claudication, anastomoticproliferation (for vein and artificial grafts), bile duct obstruction,ureter obstruction, tumor obstruction, or combinations of these.

BRIEF DESCRIPTION FO THE DRAWINGS

FIG. 1. In-vivo degradation data of terpolymer PLLA-GA-CL (60115/25).

FIG. 2. Drug Release for terpolymer PDLA-GA-CL (60/15/25) with variousD:P ratios after cold a-beam sterilization. The stents were formulatedfrom acetone/NMK (90/10).

FIG. 3 shows SEM images of a coating formed of a terpolymer PDLA-GA-CL(100 μg/CM² dose, D:P=1:3)

FIG. 4 shows SEM images for a coating formed of terpolymerPLLA-GA-CL-60/15/25 after E-beam sterilization.

DETAILED DESCRIPTION

The present invention provides an implantable device. The implantabledevice comprises a coating comprising a layer comprising a terpolymer.The terpolymer comprises caprolactone, glycolide and a third monomere,which terpolymer has a molar composition where caprolactone is about 20%or higher, and glycolide is about 10% or higher. In some embodiments,the third monomer is a lactide, e.g., D,L-lactide, L-lactide, orracemic-D,L-lactide.

In some embodiments, optionally with one or any combination of featuresof the various embodiments above or below, the terpolymer has a glasstransition temperature (T_(g)) less than 37° C.

In some embodiments, optionally with one or any combination of featuresof the various embodiments above or below, the the coating maintains itsintegrity after ethylene oxide (ETO) sterilization or e-beam treatment.

In some embodiments, optionally with one or any combination of featuresof the various embodiments above or below, the coating can have variousthickness. In some embodiments, the coating has a thickness of about 5microns or less and a degradation or absorption rate that within aperiod of 6 months after deployment of the implantable device, thecoating has a mass loss of about 80% or more.

In some embodiments, optionally with one or any combination of featuresof the various embodiments above or below, the coating can comprises aprimer comprising a biodegradable amorphous polymer.

A coating including these layers has improved coating integrity whilemaintaining mechanical integrity after EtO sterilization. In addition,the amorphous polymer can have a rate of degradation or absorptionfaster or slower than the reservoir layer, and thus, the length of thetime of bioabsorption of a coating comprising the layer comprising theterpolymer comprising caprolactone and glycolide and a primer layercomprising an amorphous layer can be tailored by the difference of rateof absorption of the amorphous primer layer and the semi-crystallinelayer.

Generally, a coating described herein can degrade or absorb at a ratethat the coating will have about 80% or more mass loss within a periodof 6 months after deployment (e.g., implanted in a blood vessel of apatient). In some embodiments, the coating mass loss within the sameperiod can be about 90% or more, 95% or more, or about 99% or more. Insome embodiments, the coating can substantially or completely degradewithin about 24 months, within about 18 months, within about 12 months,without about 9 months, within about 6 months, within about 4 months,within about 3 months, within about 2 months, or within about 1 monthafter implantation of a medical device comprising the coating. In someembodiments, the coating can substantially or completely degrade orabsorb within about 100 days after deployment.

In some embodiments, optionally with one or any combination of featuresof the various embodiments above or below, the coating can furthercomprise a bioactive agent and provides a controlled release of thebioactive agent when the implantable device is deployed. Examples of thebioactive agent are paclitaxel, docetaxel, estradiol, 17-beta-estradiol,nitric oxide donors, super oxide dismutases, super oxide dismutasemimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),biolimus, tacrolimus, dexamethasone, dexamethasone derivatives,glucocorticoids, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), temsirolimus, deforolimus,γ-hiridun, clobetasol, pimecrolimus, imatinib mesylate, midostaurin,feno fibrate, prodrugs thereof, co-drugs thereof, and combinationsthereof. Some other examples of the bioactive agent include siRNA and/orother oligonucleotides that inhibit endothelial cell migration. Somefurther examples of the bioactive agent can also be lysophosphatidicacid (LPA) or sphingosine-1-phosphate (SIP). LPA is a “bioactive”phospholipid able to generate growth factor-like activities in a widevariety of normal and malignant cell types. LPA plays an important rolein normal physiological processes such as wound healing, and in vasculartone, vascular integrity, or reproduction.

In some embodiments, optionally with one or any combination of featuresof the various embodiments above or below, the coating a degradation orabsorption rate that within a period of about 100 days after deploymentof the implantable device, the coating has a mass loss of about 80% ormore. In some embodiments, the coating has a mass loss of about 100%within 100 days or 180 days after deployment of the implantable device.

In some embodiments, optionally with one or any combination of featuresof the various embodiments above or below, the implantable device is astent or a a bioabsorbable stent.

The present invention also provides a method of fabricating animplantable device. The method generally comprises forming a coating ofthe various embodiments described above or below.

The amorphous polyester polymer can be selected to be partially orcompletely miscible with the reservoir layer such that the reservoirlayer and the primer layer can have good compatibility. In someembodiments, a miscibility of at least 5%, 10%, 20%, 30%, 40%, 50%, 70%,90%, or 95% of the primer polymer in the reservoir polymer is selected.

In some embodiments, the amorphous polymer for forming the primer layercan be selected to have a glass-transition temperature (T_(g)) lowerthan the T_(g) of the reservoir polymer.

As used herein, the term “layer comprising a terpolymer comprisingcaprolactone and glycolide” is used interchangeably with the term“terpolymer layer”, and the term “primer layer comprising an amorphouspolymer” is used interchangeably with the term “amorphous primer layer”or “amorphous layer”. In some embodiments, the term “terpolymer layer”is sometimes referred to as “reservoir layer”, and the term “amorphousprimer layer” is sometimes referred to as “primer layer.”

In some embodiments, the term “domain” can be referred to as “phase.”Therefore, the term “crystalline domain” can be referred to as“crystalline phase.” Similarly, the term “amorphous domain” can bereferred to as “amorphous phase.”

As used herein, the term “terpolymer” is used interchangeably with theterm “terpolymer comprising caprolactone and glycolide.” In someembodiments, the terpolymer comprising caprolactone and glycolide can bea copolymer formed of two or more monomers. In some embodiments, theterpolymer comprising caprolactone and glycolide can be a homopolymerformed of one monomer.

In some embodiments, the coating can include one or more otherbiocompatible polymers, which are described below.

The implantable device described herein can be formed on an implantabledevice such as a stent, which can be implanted in a patient to treat,prevent, mitigate, or reduce a vascular medical condition, or to providea pro-healing effect. In some embodiments, the vascular medicalcondition or vascular condition is a coronary artery disease (CAD)and/or a peripheral vascular disease (PVD). Some examples of suchvascular medical diseases are restenosis and/or atherosclerosis. Someother examples of these conditions include thrombosis, hemorrhage,vascular dissection or perforation, vascular aneurysm, vulnerableplaque, chronic total occlusion, claudication, anastomotic proliferation(for vein and artificial grafts), bile duct obstruction, ureterobstruction, tumor obstruction, or combinations of these.

Definitions

Wherever applicable, the definitions to some terms used throughout thedescription of the present invention as provided below shall apply.

The terms “biologically degradable” (or “biodegradable”), “biologicallyerodable” (or “bioerodable”), “biologically absorbable” (or“bioabsorbable”), and “biologically resorbable” (or “bioresorbable”), inreference to polymers and coatings, are used interchangeably and referto polymers and coatings that are capable of being completely orsubstantially completely degraded, dissolved, and/or eroded over timewhen exposed to physiological conditions and can be gradually resorbed,absorbed and/or eliminated by the body, or that can be degraded intofragments that can pass through the kidney membrane of an animal (e.g.,a human), e.g., fragments having a molecular weight of about 40,000Daltons (40 kDa) or less. The process of breaking down and eventualabsorption and elimination of the polymer or coating can be caused by,e.g., hydrolysis, metabolic processes, oxidation, enzymatic processes,bulk or surface erosion, and the like. Conversely, a “biostable” polymeror coating refers to a polymer or coating that is not biodegradable.

Whenever the reference is made to “biologically degradable,”“biologically erodable,” “biologically absorbable,” and “biologicallyresorbable” stent coatings or polymers forming such stent coatings, itis understood that after the process of degradation, erosion,absorption, and/or resorption has been completed or substantiallycompleted, no coating or substantially little coating will remain on thestent. Whenever the terms “degradable,” “biodegradable,” or“biologically degradable” are used in this application, they areintended to broadly include biologically degradable, biologicallyerodable, biologically absorbable, and biologically resorbable polymersor coatings.

“Physiological conditions” refer to conditions to which an implant isexposed within the body of an animal (e.g., a human). Physiologicalconditions include, but are not limited to, “normal” body temperaturefor that species of animal (approximately 37° C. for a human) and anaqueous environment of physiologic ionic strength, pH and enzymes. Insome cases, the body temperature of a particular animal may be above orbelow what would be considered “normal” body temperature for thatspecies of animal. For example, the body temperature of a human may beabove or below approximately 37° C. in certain cases. The scope of thepresent invention encompasses such cases where the physiologicalconditions (e.g., body temperature) of an animal are not considered“normal.”

In the context of a blood-contacting implantable device, a “prohealing”drug or agent refers to a drug or agent that has the property that itpromotes or enhances re-endothelialization of arterial lumen to promotehealing of the vascular tissue.

As used herein, a “co-drug” is a drug that is administered concurrentlyor sequentially with another drug to achieve a particularpharmacological effect. The effect may be general or specific. Theco-drug may exert an effect different from that of the other drug, or itmay promote, enhance or potentiate the effect of the other drug.

As used herein, the term “prodrug” refers to an agent rendered lessactive by a chemical or biological moiety, which metabolizes into orundergoes in vivo hydrolysis to form a drug or an active ingredientthereof. The term “prodrug” can be used interchangeably with terms suchas “proagent”, “latentiated drugs”, “bioreversible derivatives”, and“congeners”. N. J. Harper, Drug latentiation, Prog Drug Res., 4: 221-294(1962); E. B. Roche, Design of Biopharmaceutical Properties throughProdrugs and Analogs, Washington, D.C.: American PharmaceuticalAssociation (1977); A. A. Sinkula and S. H. Yalkowsky, Rationale fordesign of biologically reversible drug derivatives: prodrugs, J. Pharm.Sci., 64: 181-210 (1975). Use of the term “prodrug” usually implies acovalent link between a drug and a chemical moiety, though some authorsalso use it to characterize some forms of salts of the active drugmolecule. Although there is no strict universal definition of a prodrugitself, and the definition may vary from author to author, prodrugs cangenerally be defined as pharmacologically less active chemicalderivatives that can be converted in vivo, enzymatically ornonenzymatically, to the active, or more active, drug molecules thatexert a therapeutic, prophylactic or diagnostic effect. Sinkula andYalkowsky, above; V. J. Stella et al., Prodrugs: Do they have advantagesin clinical practice?, Drugs, 29: 455-473 (1985).

The terms “polymer” and “polymeric” refer to compounds that are theproduct of a polymerization reaction. These terms are inclusive ofhomopolymers (i.e., polymers obtained by polymerizing one type ofmonomer), copolymers (i.e., polymers obtained by polymerizing two ormore different types of monomers), terpolymers, etc., including random,alternating, block, graft, dendritic, crosslinked and any othervariations thereof.

As used herein, the term “implantable” refers to the attribute of beingimplantable in a mammal (e.g., a human being or patient) that meets themechanical, physical, chemical, biological, and pharmacologicalrequirements of a device provided by laws and regulations of agovernmental agency (e.g., the U.S. FDA) such that the device is safeand effective for use as indicated by the device. As used herein, an“implantable device” may be any suitable substrate that can be implantedin a human or non-human animal. Examples of implantable devices include,but are not limited to, self-expandable stents, balloon-expandablestents, coronary stents, peripheral stents, stent-grafts, catheters,other expandable tubular devices for various bodily lumen or orifices,grafts, vascular grafts, arterio-venous grafts, by-pass grafts,pacemakers and defibrillators, leads and electrodes for the preceding,artificial heart valves, anastomotic clips, arterial closure devices,patent foramen ovale closure devices, cerebrospinal fluid shunts, andparticles (e.g., drug-eluting particles, microparticles andnanoparticles). The stents may be intended for any vessel in the body,including neurological, carotid, vein graft, coronary, aortic, renal,iliac, femoral, popliteal vasculature, and urethral passages. Animplantable device can be designed for the localized delivery of atherapeutic agent. A medicated implantable device may be constructed inpart, e.g., by coating the device with a coating material containing atherapeutic agent. The body of the device may also contain a therapeuticagent.

An implantable device can be fabricated with a coating containingpartially or completely a biodegradable/bioabsorbable/bioerodablepolymer, a biostable polymer, or a combination thereof. An implantabledevice itself can also be fabricated partially or completely from abiodegradable/bioabsorbable/bioerodable polymer, a biostable polymer, ora combination thereof.

As used herein, a material that is described as a layer or a film (e.g.,a coating) “disposed over” an indicated substrate (e.g., an implantabledevice) refers to, e.g., a coating of the material deposited directly orindirectly over at least a portion of the surface of the substrate.Direct depositing means that the coating is applied directly to theexposed surface of the substrate. Indirect depositing means that thecoating is applied to an intervening layer that has been depositeddirectly or indirectly over the substrate. In some embodiments, the terma “layer” or a “film” excludes a film or a layer formed on anon-implantable device.

In the context of a stent, “delivery” refers to introducing andtransporting the stent through a bodily lumen to a region, such as alesion, in a vessel that requires treatment. “Deployment” corresponds tothe expanding of the stent within the lumen at the treatment region.Delivery and deployment of a stent are accomplished by positioning thestent about one end of a catheter, inserting the end of the catheterthrough the skin into a bodily lumen, advancing the catheter in thebodily lumen to a desired treatment location, expanding the stent at thetreatment location, and removing the catheter from the lumen.

Terpolymer Composition

The terpolymer described herein can have different contents ofcaprolactone (A), glycolide (B), and a third monomer (C). The terpolymercan be expressed in this general formula A_(x)B_(y)C_(z), wherein x, yand z are ratios of A, B, and C, respectively. Within the terpolymer,monomers A, B, and C can have any sequence of arrangement, for example,ABC, BAC, CBA, ACB, ABAC, ABBC, BABC, BAAC, BACC, CBCA, CBBA, CBAA,ABACA, ABACB, ABACC, BABCA, BABCB, BABCC, etc. As outlined in someembodiments, a sequence of monomers or units can have more than oneunits of a monomer, which are described in more detail below.

Terpolymers with different contents of these three monomers havedifferent properties with regard to, e.g., rate of degradation,mechanical properties, drug permeability, water permeability, and drugrelease rate, depending on a particular composition of the monomers inthe terpolymer.

The terpolymer can have a composition having caprolactone in a molarratio of about 20% or higher and a glycolide in a molar ratio of about10% or higher. Therefore, the terpolymer can have the third monomer in amolar ratio of about 70% or lower. In some embodiments, this terpolymercan have a third monomer such as a lactide, e.g., D-lactide, L-lactide,D,L-lactide, racemic-D,L-lactide.

In some embodiments, the terpolymer can have a T_(g) below about 37° C.

Ratios of units from the caprolactone, glycolide and the third monomerscan vary, forming a terpolymer having different properties, e.g.,different degradation rates, different rates of release of a drug from acoating formed of the terpolymer, different drug permeability, differentflexibility or mechanical properties. For example, the glycolideprovides an accelerated or enhanced degradation of the terpolymer, thelactide monomer, if present as the third monomer, provides mechanicalstrength to the terpolymer, and the caprolactone monomer can lower theT_(g) of the terpolymer and enhance drug permeability, waterpermeability, and enhancing degradation rate of the polymer, impartinggreater flexibility and elongation, and improving mechanical propertiesof a coating formed of the terpolymer.

In some embodiments, the ratio of the various monomers can vary alongthe chain of the terpolymer. In such a terpolymer, one point of thechain of polymer can be heavy with one monomer while another point ofthe chain can be light with the same monomer, for example. If amonofunctional initiator is used, and if the selected monomers havehighly different reactivity ratios, then a gradient of composition isgenerated as the monomers are consumed during the polymerization. Inanother methodology, such a terpolymer can be prepared by so-calledgradient polymerization wherein during the polymerization a first orsecond monomer is progressively added to the reactor containing all, ora portion of, the first monomer. (Matyjaszewski K. and Davis T. P. eds.Handbook of Radical Polymerization, John Wiley & Sons, 2002, p. 789).Yet a third method is by introducing blocks of various ratios of themonomers into the chain of the terpolymer.

In some embodiments, the terpolymer described herein can be used tobuild one or more blocks in combination with other blocks such aspoly(ethylene glycol) (PEG) or other blocks of biodegradable orbiodurable polymers described below.

Randomness of the terpolymer described herein can be measured byrandomness index. Generally, a perfectly alternating co-polymer wouldhave a degree of randomness of 1. Conversely, in some embodiments, theterpolymer can include all the repeating units of the monomers in threeblocks, the lactide block, the glycolide block, and the block of thethird, low T_(g) monomer. Such a terpolymer would have a degree ofrandomness of 0. These are known as block copolymers. In some otherembodiments, the terpolymer can have a degree of randomness ranging fromabove 0 to below 1, for example, about 0.01, about 0.02, about 0.05,about 0.1, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4,about 0.45, about 0.5, about 0.55, about 0.6, about 0.65, about 0.7,about 0.75, about 0.8, about 0.85, about 0.9, about 0.95, or about 0.99.Generally, for a crystalline domain to develop, one usually needs apentad (i.e. the same 5 repeat units or monomers in sequence).Therefore, in some embodiments, one factor to control the randomness ofthe terpolymer is to keep the repeat units or monomers in sequence inthe terpolymer below 5, e.g., 1, 2, 3, or 4.

Randomness in a polymer can be readily determined by establishedtechniques in the art. One such technique is NMR analysis ((see, e.g.,J. Kasperczyk, Polymer, 37(2):201-203 (1996); Mangkorn Srisa-ard, etal., Polym Int., 50:891-896 (2001)).

Randomness of an amorphous terpolymer can be readily controlled orvaried using techniques known in the art. For example, randomness in abatch reactor is controlled by polymerization temperature and type ofsolvent where the monomer reactivity ratios will change. For continuousreactors, it will also depend on monomer feed ratios and temperature.Secondarily, there is also a pressure effect on reactivity ratios.Monomers relative reactivity is also important, so you can control it byselecting monomers with similar or different reactivity.

Amorphous Polymers

The amorphous primer layer can be formed of any one or more amorphouspolymer(s). In some embodiments, the amorphous polymer is an amorphouspolyester polymer. Some examples of amorphous polyesters include, butare not limited to:

-   -   amorphous poly(D,L-lactide) (PDLA);    -   amorphous poly(L-lactide-co-D,L-lactide) (PLLLA) with        D,L-lactide content of about 30 molar % or above;    -   amorphous poly(D,L-lactide-co-glycolide) (PDLGA) with glycolide        content of about 10 to about 50 molar %;    -   amorphous poly(L-lactide-co-glycolide) (PLLGA) with L-lactide        content of about 70 molar % or below;    -   amorphous poly(glycolide-co-caprolactone) (PGACL) with glycolide        content of about 70 molar % or below;    -   amorphous poly(D,L-lactide-co-caprolactone) (PDLACL) with        caprolactone content of about 70 molar % or below;    -   amorphous poly(L-lactide-co-caprolactone) (PLLACL) with        L-lactide content of below 70 molar % but above 30 molar %;    -   amorphous copolymers of trimethylene carbonate with glycolide,        D,L-lactide, and/or L-lactide; and    -   amorphous PDLGA-CL and PLLA-GA-CL terpolymers with content of        L-lactide of about 65 molar % or below.

The amorphous polymers can have different molecular weights. In someembodiments, the amorphous polymers listed above can have a weightaverage molecular weight (Mw) between about 75K Daltons to about 200KDaltons.

The primer polymer can be selected to degrade more slowly than thereservoir layer. In some embodiments, it can be selected to degrade orabsorb faster than the reservoir layer. In some embodiments, the primerlayer can degrade or absorb completely or substantially completelywithin about 6 months after deployment.

In some embodiments, the amorphous polymer can be subjected todegradation modulation to bring the overall coating degradation orabsorption rate within a desired range. One example of such modulatingthe degradation or absorption rate of the amorphous polymer is tosubject the polymer to E-beam or gamma irradiation treatment, which is aprocedure well known in the art.

As used herein, the term “substantially completely” shall mean about 20%or less than 20% by weight of polymer residue remains. In someembodiments, the term shall mean less than about 10% by weight ofpolymer residue remains. In some further embodiments, the term shallmean less than 5% or 1% by weight of polymer residue remains.

Biologically Active Agents

In some embodiments, the implantable device described herein canoptionally include at least one biologically active (“bioactive”) agent.The at least one bioactive agent can include any substance capable ofexerting a therapeutic, prophylactic or diagnostic effect for a patient.

Examples of suitable bioactive agents include, but are not limited to,synthetic inorganic and organic compounds, proteins and peptides,polysaccharides and other sugars, lipids, and DNA and RNA nucleic acidsequences having therapeutic, prophylactic or diagnostic activities.Nucleic acid sequences include genes, antisense molecules that bind tocomplementary DNA to inhibit transcription, and ribozymes. Some otherexamples of other bioactive agents include antibodies, receptor ligands,enzymes, adhesion peptides, blood clotting factors, inhibitors or clotdissolving agents such as streptokinase and tissue plasminogenactivator, antigens for immunization, hormones and growth factors,oligonucleotides such as antisense oligonucleotides and ribozymes andretroviral vectors for use in gene therapy. The bioactive agents couldbe designed, e.g., to inhibit the activity of vascular smooth musclecells. They could be directed at inhibiting abnormal or inappropriatemigration and/or proliferation of smooth muscle cells to inhibitrestenosis.

In certain embodiments, optionally in combination with one or more otherembodiments described herein, the implantable device can include atleast one biologically active agent selected from antiproliferative,antineoplastic, antimitotic, anti-inflammatory, antiplatelet,anticoagulant, antifibrin, antithrombin, antibiotic, antiallergic andantioxidant substances.

An antiproliferative agent can be a natural proteineous agent such as acytotoxin or a synthetic molecule. Examples of antiproliferativesubstances include, but are not limited to, actinomycin D or derivativesand analogs thereof (manufactured by Sigma-Aldrich, or COSMEGENavailable from Merck) (synonyms of actinomycin D include dactinomycin,actinomycin IV, actinomycin I₁, actinomycin X₁, and actinomycin C₁); alltaxoids such as taxols, docetaxel, and paclitaxel and derivativesthereof; all olimus drugs such as macrolide antibiotics, rapamycin,everolimus, structural derivatives and functional analogues ofrapamycin, structural derivatives and functional analogues ofeverolimus, FKBP-12 mediated mTOR inhibitors, biolimus, perfenidone,prodrugs thereof, co-drugs thereof, and combinations thereof. Examplesof rapamycin derivatives include, but are not limited to,40-O-(2-hydroxy)ethyl-rapamycin (trade name everolimus from Novartis),40-O-(2-ethoxy)ethyl-rapamycin (biolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (zotarolimus, manufactured by AbbottLabs.), deforolimus, temsirolimus, prodrugs thereof, co-drugs thereof,and combinations thereof. An anti-inflammatory drug can be a steroidalanti-inflammatory drug, a nonsteroidal anti-inflammatory drug (NSAID),or a combination thereof. Examples of anti-inflammatory drugs include,but are not limited to, alclofenac, alclometasone dipropionate,algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenacsodium, amiprilose hydrochloride, anakinra, anirolac, anitrazafen,apazone, balsalazide disodium, bendazac, benoxaprofen, benzydaminehydrochloride, bromelains, broperamole, budesonide, carprofen,cicloprofen, cintazone, cliprofen, clobetasol, clobetasol propionate,clobetasone butyrate, clopirac, cloticasone propionate, cormethasoneacetate, cortodoxone, deflazacort, desonide, desoximetasone,dexamethasone, dexamethasone derivatives, glucocorticoids, dexamethasoneacetate, dexamethasone dipropionate, diclofenac potassium, diclofenacsodium, diflorasone diacetate, diflumidone sodium, diflunisal,difluprednate, diftalone, dimethyl sulfoxide, drocinonide, endrysone,enlimomab, enolicam sodium, epirizole, etodolac, etofenamate, felbinac,fenamole, fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone,fentiazac, flazalone, fluazacort, flufenamic acid, flumizole,flunisolide acetate, flunixin, flunixin meglumine, fluocortin butyl,fluorometholone acetate, fluquazone, flurbiprofen, fluretofen,fluticasone propionate, furaprofen, furobufen, halcinonide, halobetasolpropionate, halopredone acetate, ibufenac, ibuprofen, ibuprofenaluminum, ibuprofen piconol, ilonidap, indomethacin, indomethacinsodium, indoprofen, indoxole, intrazole, isoflupredone acetate,isoxepac, isoxicam, ketoprofen, lofemizole hydrochloride, lomoxicam,loteprednol etabonate, meclofenamate sodium, meclofenamic acid,meclorisone dibutyrate, mefenamic acid, mesalamine, meseclazone,methylprednisolone suleptanate, momiflumate, nabumetone, naproxen,naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein,orpanoxin, oxaprozin, oxyphenbutazone, paranyline hydrochloride,pentosan polysulfate sodium, phenbutazone sodium glycerate, pirfenidone,piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen,prednazate, prifelone, prodolic acid, proquazone, proxazole, proxazolecitrate, rimexolone, romazarit, salcolex, salnacedin, salsalate,sanguinarium chloride, seclazone, sermetacin, sudoxicam, sulindac,suprofen, talmetacin, talniflumate, talosalate, tebufelone, tenidap,tenidap sodium, tenoxicam, tesicam, tesimide, tetrydamine, tiopinac,tixocortol pivalate, tolmetin, tolmetin sodium, triclonide,triflumidate, zidometacin, zomepirac sodium, aspirin (acetylsalicylicacid), salicylic acid, corticosteroids, glucocorticoids, tacrolimus,pimecorlimus, prodrugs thereof, co-drugs thereof, and combinationsthereof.

Alternatively, the anti-inflammatory agent can be a biological inhibitorof pro-inflammatory signaling molecules. Anti-inflammatory biologicalagents include antibodies to such biological inflammatory signalingmolecules.

In addition, the bioactive agents can be other than antiproliferative oranti-inflammatory agents. The bioactive agents can be any agent that isa therapeutic, prophylactic or diagnostic agent. In some embodiments,such agents can be used in combination with antiproliferative oranti-inflammatory agents. These bioactive agents can also haveantiproliferative and/or anti-inflammatory properties or can have otherproperties such as antineoplastic, antimitotic, cystostatic,antiplatelet, anticoagulant, antifibrin, antithrombin, antibiotic,antiallergic, and/or antioxidant properties.

Examples of antineoplastics and/or antimitotics include, but are notlimited to, paclitaxel (e.g., TAXOL® available from Bristol-MyersSquibb), docetaxel (e.g., Taxotere® from Aventis), methotrexate,azathioprine, vincristine, vinblastine, fluorouracil, doxorubicinhydrochloride (e.g., Adriamycin® from Pfizer), and mitomycin (e.g.,Mutamycin® from Bristol-Myers Squibb).

Examples of antiplatelet, anticoagulant, antifibrin, and antithrombinagents that can also have cytostatic or antiproliferative propertiesinclude, but are not limited to, sodium heparin, low molecular weightheparins, heparinoids, hirudin, argatroban, forskolin, vapiprost,prostacyclin and prostacyclin analogues, dextran,D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole,glycoprotein IIb/IIIa platelet membrane receptor antagonist antibody,recombinant hirudin, thrombin inhibitors such as ANGIOMAX (from Biogen),calcium channel blockers (e.g., nifedipine), colchicine, fibroblastgrowth factor (FGF) antagonists, fish oil (e.g., omega 3-fatty acid),histamine antagonists, lovastatin (a cholesterol-lowering drug thatinhibits HMG-CoA reductase, brand name Mevacor® from Merck), monoclonalantibodies (e.g., those specific for platelet-derived growth factor(PDGF) receptors), nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitors, suramin, serotonin blockers, steroids,thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), nitricoxide or nitric oxide donors, super oxide dismutases, super oxidedismutase mimetics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), estradiol, anticancer agents, dietary supplements suchas various vitamins, and a combination thereof.

Examples of cytostatic substances include, but are not limited to,angiopeptin, angiotensin converting enzyme inhibitors such as captopril(e.g., Capoten® and Capozide® from Bristol-Myers Squibb), cilazapril andlisinopril (e.g., Prinivil® and Prinzide® from Merck).

Examples of antiallergic agents include, but are not limited to,permirolast potassium. Examples of antioxidant substances include, butare not limited to, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO). Other bioactive agents include anti-infectives such asantiviral agents; analgesics and analgesic combinations; anorexics;antihelmintics; antiarthritics, antiasthmatic agents; anticonvulsants;antidepressants; antidiuretic agents; antidiarrheals; antihistamines;antimigrain preparations; antinauseants; antiparkinsonism drugs;antipruritics; antipsychotics; antipyretics; antispasmodics;anticholinergics; sympathomimetics; xanthine derivatives; cardiovascularpreparations including calcium channel blockers and beta-blockers suchas pindolol and antiarrhythmics; antihypertensives; diuretics;vasodilators including general coronary vasodilators; peripheral andcerebral vasodilators; central nervous system stimulants; cough and coldpreparations, including decongestants; hypnotics; immunosuppressives;muscle relaxants; parasympatholytics; psychostimulants; sedatives;tranquilizers; naturally derived or genetically engineered lipoproteins;and restenoic reducing agents.

Other biologically active agents that can be used includealpha-interferon, genetically engineered epithelial cells, tacrolimusand dexamethasone.

A “prohealing” drug or agent, in the context of a blood-contactingimplantable device, refers to a drug or agent that has the property thatit promotes or enhances re-endothelialization of arterial lumen topromote healing of the vascular tissue. The portion(s) of an implantabledevice (e.g., a stent) containing a prohealing drug or agent canattract, bind and eventually become encapsulated by endothelial cells(e.g., endothelial progenitor cells). The attraction, binding, andencapsulation of the cells will reduce or prevent the formation ofemboli or thrombi due to the loss of the mechanical properties thatcould occur if the stent was insufficiently encapsulated. The enhancedre-endothelialization can promote the endothelialization at a ratefaster than the loss of mechanical properties of the stent.

The prohealing drug or agent can be dispersed in the body of thebioabsorbable polymer substrate or scaffolding. The prohealing drug oragent can also be dispersed within a bioabsorbable polymer coating overa surface of an implantable device (e.g., a stent).

“Endothelial progenitor cells” refer to primitive cells made in the bonemarrow that can enter the bloodstream and go to areas of blood vesselinjury to help repair the damage. Endothelial progenitor cells circulatein adult human peripheral blood and are mobilized from bone marrow bycytokines, growth factors, and ischemic conditions. Vascular injury isrepaired by both angiogenesis and vasculogenesis mechanisms. Circulatingendothelial progenitor cells contribute to repair of injured bloodvessels mainly via a vasculogenesis mechanism.

In some embodiments, the prohealing drug or agent can be an endothelialcell (EDC)-binding agent. In certain embodiments, the EDC-binding agentcan be a protein, peptide or antibody, which can be, e.g., one ofcollagen type 1, a 23 peptide fragment known as single chain Fv fragment(scFv A5), a junction membrane protein vascular endothelial(VE)-cadherin, and combinations thereof. Collagen type 1, when bound toosteopontin, has been shown to promote adhesion of endothelial cells andmodulate their viability by the down regulation of apoptotic pathways.S. M. Martin, et al., J. Biomed. Mater. Res., 70A:10-19 (2004).Endothelial cells can be selectively targeted (for the targeted deliveryof immunoliposomes) using scFv A5. T. Volkel, et al., Biochimica etBiophysica Acta, 1663:158-166 (2004). Junction membrane protein vascularendothelial (VE)-cadherin has been shown to bind to endothelial cellsand down regulate apoptosis of the endothelial cells. R. Spagnuolo, etal., Blood, 103:3005-3012 (2004).

In a particular embodiment, the EDC-binding agent can be the activefragment of osteopontin,(Asp-Val-Asp-Val-Pro-Asp-Gly-Asp-Ser-Leu-Ala-Try-Gly). Other EDC-bindingagents include, but are not limited to, EPC (epithelial cell)antibodies, RGD peptide sequences, RGD mimetics, and combinationsthereof.

In further embodiments, the prohealing drug or agent can be a substanceor agent that attracts and binds endothelial progenitor cells.Representative substances or agents that attract and bind endothelialprogenitor cells include antibodies such as CD-34, CD-133 and vegf type2 receptor. An agent that attracts and binds endothelial progenitorcells can include a polymer having nitric oxide donor groups.

The foregoing biologically active agents are listed by way of exampleand are not meant to be limiting. Other biologically active agents thatare currently available or that may be developed in the future areequally applicable.

In a more specific embodiment, optionally in combination with one ormore other embodiments described herein, the implantable device of theinvention comprises at least one biologically active agent selected frompaclitaxel, docetaxel, estradiol, nitric oxide donors, super oxidedismutases, super oxide dismutase mimics,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),tacrolimus, dexamethasone, dexamethasone derivatives, glucocorticoids,rapamycin, rapamycin derivatives, 40-O-(2-hydroxy)ethyl-rapamycin(everolimus), 40-O-(2-ethoxy)ethyl-rapamycin (biolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (zotarolimus), temsirolimus,deforolimus, pimecrolimus, imatinib mesylate, midostaurin, clobetasol,progenitor cell-capturing antibodies, prohealing drugs, prodrugsthereof, co-drugs thereof, and a combination thereof. In a particularembodiment, the bioactive agent is everolimus. In another specificembodiment, the bioactive agent is clobetasol.

An alternative class of drugs would be p-para-α-agonists for increasedlipid transportation, examples include fenofibrate.

In some embodiments, optionally in combination with one or more otherembodiments described herein, the at least one biologically active agentspecifically cannot be one or more of any of the bioactive drugs oragents described herein.

Coating Construct

According to some embodiments of the invention, optionally incombination with one or more other embodiments described herein, acoating disposed over an implantable device (e.g., a stent) can includea terpolymer comprising caprolactone and glycolide in the reservoirlayer and an amorphous polymer in the primer layer described herein in alayer according to any design of a coating. The coating can be amulti-layer structure that includes at least one primer layer, which islayer (1) described below, and at least one reservoir layer, which islayer (2) described below, and can include any of the following (3), (4)and (5) layers or combination thereof:

-   -   (1) a primer layer;    -   (2) a reservoir layer (also referred to “matrix layer” or “drug        matrix”), which can be a drug-polymer layer including at least        one polymer (drug-polymer layer) or, alternatively, a        polymer-free drug layer;    -   (3) a release control layer (also referred to as a        “rate-limiting layer”);    -   (4) a topcoat layer; and/or    -   (5) a finishing coat layer.

In some embodiments, a coating of the invention can include two or morereservoir layers described above, each of which can include a bioactiveagent described herein.

Each layer of a coating can be disposed over the implantable device(e.g., a stent) by dissolving the terpolymer comprising caprolactone andglycolide, optionally with one or more other polymers, in a solvent, ora mixture of solvents, and disposing the resulting coating solution overthe stent by spraying or immersing the stent in the solution. After thesolution has been disposed over the stent, the coating is dried byallowing the solvent to evaporate. The process of drying can beaccelerated if the drying is conducted at an elevated temperature. Thecomplete stent coating can be optionally annealed at a temperaturebetween about 40° C. and about 150° C. for a period of time betweenabout 5 minutes and about 60 minutes, if desired, to allow forcrystallization of the polymer coating, and/or to improve thethermodynamic stability of the coating.

To incorporate a bioactive agent (e.g., a drug) into the reservoirlayer, the drug can be combined with the polymer solution that isdisposed over the implantable device as described above. Alternatively,if it is desirable a polymer-free reservoir can be made. To fabricate apolymer-free reservoir, the drug can be dissolved in a suitable solventor mixture of solvents, and the resulting drug solution can be disposedover the implantable device (e.g., stent) by spraying or immersing thestent in the drug-containing solution.

Instead of introducing a drug via a solution, the drug can be introducedas a colloid system, such as a suspension in an appropriate solventphase. To make the suspension, the drug can be dispersed in the solventphase using conventional techniques used in colloid chemistry. Dependingon a variety of factors, e.g., the nature of the drug, those havingordinary skill in the art can select the solvent to form the solventphase of the suspension, as well as the quantity of the drug to bedispersed in the solvent phase. Optionally, a surfactant can be added tostabilize the suspension. The suspension can be mixed with a polymersolution and the mixture can be disposed over the stent as describedabove. Alternatively, the drug suspension can be disposed over the stentwithout being mixed with the polymer solution.

The drug-polymer layer can be applied indirectly over at least a portionof the stent surface to serve as a reservoir for at least one bioactiveagent (e.g., drug) that is incorporated into the reservoir layer over atleast a portion of the primer layer. The primer layer can be appliedbetween the stent and the reservoir to improve the adhesion of thedrug-polymer layer to the stent. The optional topcoat layer can beapplied over at least a portion of the reservoir layer and serves as arate-limiting membrane that helps to control the rate of release of thedrug. In one embodiment, the topcoat layer can be essentially free fromany bioactive agents or drugs. If the topcoat layer is used, theoptional finishing coat layer can be applied over at least a portion ofthe topcoat layer for further control of the drug-release rate and forimproving the biocompatibility of the coating. Without the topcoatlayer, the finishing coat layer can be deposited directly on thereservoir layer.

Sterilization of a coated medical device generally involves a processfor inactivation of micropathogens. Such processes are well known in theart. A few examples are e-beam, ETO sterilization, autoclaving, andgamma irradiation. Most, if not all, of these processes can involve anelevated temperature. For example, ETO sterilization of a coated stentgenerally involves heating above 50° C. at humidity levels reaching upto 100% for periods of a few hours up to 24 hours. A typical EtO cyclewould have the temperature in the enclosed chamber to reach as high asabove 50° C. within the first 3-4 hours then and fluctuate between 40°C. to 50° C. for 17-18 hours while the humidity would reach the peak at100% and maintain above 80% during the fluctuation time of the cycle.

The process of the release of a drug from a coating having both topcoatand finishing coat layers includes at least three steps. First, the drugis absorbed by the polymer of the topcoat layer at the drug-polymerlayer/topcoat layer interface. Next, the drug diffuses through thetopcoat layer using the void volume between the macromolecules of thetopcoat layer polymer as pathways for migration. Next, the drug arrivesat the topcoat layer/finishing layer interface. Finally, the drugdiffuses through the finishing coat layer in a similar fashion, arrivesat the outer surface of the finishing coat layer, and desorbs from theouter surface. At this point, the drug is released into the blood vesselor surrounding tissue. Consequently, a combination of the topcoat andfinishing coat layers, if used, can serve as a rate-limiting barrier.The drug can be released by virtue of the degradation, dissolution,and/or erosion of the layer(s) forming the coating, or via migration ofthe drug through the terpolymer comprising caprolactone and glycolideiclayer(s) into a blood vessel or tissue.

In one embodiment, except for the primer layer, any or all of otherlayers of the stent coating can be made of a terpolymer comprisingcaprolactone and glycolide described herein, optionally having theproperties of being biologicallydegradable/erodable/absorbable/resorbable, non-degradable/biostablepolymer, or a combination thereof.

In another embodiment, except for the reservoir layer, any or all ofother layers of the stent coating can be made of an amorphous polymerdescribed herein, optionally having the properties of being biologicallydegradable/erodable/absorbable/resorbable, non-degradable/biostablepolymer, or a combination thereof.

If a finishing coat layer is not used, the topcoat layer can be theoutermost layer and can be made of a terpolymer comprising caprolactoneand glycolide and/or an amorphous polymer described herein andoptionally having the properties of being biodegradable or, biostable,or being mixed with an amorphous polymer. In this case, the remaininglayers (i.e., the primer and the reservoir layer) optionally can also befabricated of a terpolymer comprising caprolactone and glycolidedescribed herein and optionally having the properties of beingbiodegradable or, biostable, or being mixed with an amorphous polymerThe polymer(s) in a particular layer may be the same as or differentthan those in any of the other layers, as long as the outside of anotherbioabsorbable should preferably also be bioabsorbable and degrade at asimilar or faster relative to the inner layer.

If neither a finishing coat layer nor a topcoat layer is used, the stentcoating could have only two layers—the primer and the reservoir. In sucha case, the reservoir is the outermost layer of the stent coating andshould be made of a terpolymer comprising caprolactone and glycolidedescribed herein and optionally having the properties of beingbiodegradable or, biostable, or being mixed with an amorphous polymer.The primer layer is fabricated of an amorphous polymer described hereinand optionally one or more biodegradable polymer(s), biostablepolymer(s), or a combination thereof.

Any layer of a coating, except for the primer layer, can contain anyamount of a terpolymer comprising caprolactone and glycolide describedherein and optionally having the properties of being biodegradable or,biostable. Non-limiting examples of bioabsorbable polymers andbiocompatible polymers include poly(N-vinyl pyrrolidone); polydioxanone;polyorthoesters; polyanhydrides; poly(glycolic acid); poly(glycolicacid-co-trimethylene carbonate); polyphosphoesters; polyphosphoesterurethanes; poly(amino acids); poly(trimethylene carbonate);poly(iminocarbonates); co-poly(ether-esters); polyalkylene oxalates;polyphosphazenes; biomolecules, e.g., fibrin, fibrinogen, cellulose,cellophane, starch, collagen, hyaluronic acid, and derivatives thereof(e.g., cellulose acetate, cellulose butyrate, cellulose acetatebutyrate, cellulose nitrate, cellulose propionate, cellulose ethers, andcarboxymethyl cellulose), polyurethane, polyesters, polycarbonates,polyurethanes, poly(L-lactic acid-co-caprolactone) (PLLA-CL),poly(D-lactic acid-co-caprolactone) (PDLA-CL), poly(DL-lacticacid-co-caprolactone) (PDLLA-CL), poly(D-lactic acid-glycolic acid(PDLA-GA), poly(L-lactic acid-glycolic acid (PLLA-GA), poly(DL-lacticacid-glycolic acid (PDLLA-GA), poly(L-lactic acid-co-caprolactone)(PLLA-CL), poly(D-lactic acid-co-caprolactone) (PDLA-CL), poly(DL-lacticacid-co-caprolactone) (PDLLA-CL), poly(glycolide-co-caprolactone)(PGA-CL), or any copolymers thereof.

Any layer of a stent coating can also contain any amount of anon-degradable polymer, or a blend of more than one such polymer as longas it is not mixed with a bioabsorbable polymer or any layer underneaththe non-degradable layer comprise a bioabsorbable polymer. Non-limitingexamples of non-degradable polymers include poly(methylmethacrylate),poly(ethylmethacrylate), poly(butylmethacrylate),poly(2-ethylhexylmethacrylate), poly(laurylmethacrylate),poly(2-hydroxyethyl methacrylate), polyethylene glycol (PEG) acrylate,PEG methacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC) andpoly(n-vinyl pyrrolidone), poly(methacrylic acid), poly(acrylic acid),poly(hydroxypropyl methacrylate), poly(hydroxypropylmethacrylamide),poly(3-trimethylsilylpropyl methacrylate), and copolymers thereof.

Method of Fabricating Implantable Device

Other embodiments of the invention, optionally in combination with oneor more other embodiments described herein, are drawn to a method offabricating an implantable device. In one embodiment, the methodcomprises forming the implantable device of a material containing abiodegradable or biostable polymer or copolymer.

Under the method, a portion of the implantable device or the wholedevice itself can be formed of the material containing a biodegradableor biostable polymer or copolymer. The method can deposit a coatinghaving a range of thickness over an implantable device. In certainembodiments, the method deposits over at least a portion of theimplantable device a coating that has a thickness of ≦about 30 microns,or ≦about 20 microns, or ≦about 10 microns, or ≦about 5 microns.

In certain embodiments, the method is used to fabricate an implantabledevice selected from stents, grafts, stent-grafts, catheters, leads andelectrodes, clips, shunts, closure devices, valves, and particles. In aspecific embodiment, the method is used to fabricate a stent.

In some embodiments, to form an implantable device formed from apolymer, a polymer or copolymer optionally including at least onebioactive agent described herein can be formed into a polymer construct,such as a tube or sheet that can be rolled or bonded to form a constructsuch as a tube. An implantable device can then be fabricated from theconstruct. For example, a stent can be fabricated from a tube by lasermachining a pattern into the tube. In another embodiment, a polymerconstruct can be formed from the polymeric material of the inventionusing an injection-molding apparatus.

Non-limiting examples of polymers, which may or may not be theterpolymer comprising caprolactone and glycolides defined above, thatcan be used to fabricate an implantable device includepoly(N-acetylglucosamine) (Chitin), Chitosan, poly(hydroxyvalerate),poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polyorthoester, polyanhydride,poly(L-lactic acid-co-caprolactone) (PLLA-CL), poly(D-lacticacid-co-caprolactone) (PDLA-CL), poly(DL-lactic acid-co-caprolactone)(PDLLA-CL), poly(D-lactic acid-glycolic acid (PDLA-GA), poly(L-lacticacid-glycolic acid (PLLA-GA), poly(DL-lactic acid-glycolic acid(PDLLA-GA), poly(L-lactic acid-co-caprolactone) (PLLA-CL), poly(D-lacticacid-co-caprolactone) (PDLA-CL), poly(DL-lactic acid-co-caprolactone)(PDLLA-CL), poly(glycolide-co-caprolactone) (PGA-CL), poly(thioesters),poly(trimethylene carbonate), polyethylene amide, polyethylene acrylate,poly(glycolic acid-co-trimethylene carbonate), co-poly(ether-esters)(e.g., PEO/PLA), polyphosphazenes, biomolecules (e.g., fibrin,fibrinogen, cellulose, starch, collagen and hyaluronic acid),polyurethanes, silicones, polyesters, polyolefins, polyisobutylene andethylene-alphaolefin copolymers, acrylic polymers and copolymers otherthan polyacrylates, vinyl halide polymers and copolymers (e.g.,polyvinyl chloride), polyvinyl ethers (e.g., polyvinyl methyl ether),polyvinylidene halides (e.g., polyvinylidene chloride),polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics (e.g.,polystyrene), polyvinyl esters (e.g., polyvinyl acetate),acrylonitrile-styrene copolymers, ABS resins, polyamides (e.g., Nylon 66and polycaprolactam), polycarbonates, polyoxymethylenes, polyimides,polyethers, polyurethanes, rayon, rayon-triacetate, cellulose andderivates thereof (e.g., cellulose acetate, cellulose butyrate,cellulose acetate butyrate, cellophane, cellulose nitrate, cellulosepropionate, cellulose ethers, and carboxymethyl cellulose), andcopolymers thereof.

Additional representative examples of polymers that may be suited forfabricating an implantable device include ethylene vinyl alcoholcopolymer (commonly known by the generic name EVOH or by the trade nameEVAL), poly(butyl methacrylate), poly(vinylidenefluoride-co-hexafluoropropylene) (e.g., SOLEF 21508, available fromSolvay Solexis PVDF of Thorofare, N.J.), polyvinylidene fluoride(otherwise known as KYNAR, available from ATOFINA Chemicals ofPhiladelphia, Pennsylvania),poly(tetrafluoroethylene-co-hexafluoropropylene-co-vinylidene fluoride),ethylene-vinyl acetate copolymers, and polyethylene glycol.

Method of Treating or Preventing Disorders

An implantable device according to the present invention can be used totreat, prevent or diagnose various conditions or disorders. Examples ofsuch conditions or disorders include, but are not limited to,atherosclerosis, thrombosis, restenosis, hemorrhage, vasculardissection, vascular perforation, vascular aneurysm, vulnerable plaque,chronic total occlusion, patent foramen ovale, claudication, anastomoticproliferation of vein and artificial grafts, arteriovenous anastamoses,bile duct obstruction, ureter obstruction and tumor obstruction. Aportion of the implantable device or the whole device itself can beformed of the material, as described herein. For example, the materialcan be a coating disposed over at least a portion of the device.

In certain embodiments, optionally in combination with one or more otherembodiments described herein, the inventive method treats, prevents ordiagnoses a condition or disorder selected from atherosclerosis,thrombosis, restenosis, hemorrhage, vascular dissection, vascularperforation, vascular aneurysm, vulnerable plaque, chronic totalocclusion, patent foramen ovale, claudication, anastomotic proliferationof vein and artificial grafts, arteriovenous anastamoses, bile ductobstruction, ureter obstruction and tumor obstruction. In a particularembodiment, the condition or disorder is atherosclerosis, thrombosis,restenosis or vulnerable plaque.

In one embodiment of the method, optionally in combination with one ormore other embodiments described herein, the implantable device isformed of a material or includes a coating containing at least onebiologically active agent selected from paclitaxel, docetaxel,estradiol, nitric oxide donors, super oxide dismutases, super oxidedismutase mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), tacrolimus, dexamethasone, dexamethasone derivatives,glucocorticoids, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(2-ethoxy)ethyl-rapamycin (biolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (zotarolimus), temsirolimus,deforolimus, pimecrolimus, imatinib mesylate, midostaurin, clobetasol,progenitor cell-capturing antibodies, prohealing drugs, fenofibrate,prodrugs thereof, co-drugs thereof, and a combination thereof.

In certain embodiments, optionally in combination with one or more otherembodiments described herein, the implantable device used in the methodis selected from stents, grafts, stent-grafts, catheters, leads andelectrodes, clips, shunts, closure devices, valves, and particles. In aspecific embodiment, the implantable device is a stent.

EXAMPLES

The following non-limiting examples illustrate the various embodimentsdescribed above.

Coatings comprising various compositions of terpolymer of caprolactone,glycolide, and lactide were coated on stents using a solvent ofacetone/MIBK (90/10). Coatings were evaluated in a porcine coronarymodel using 10% overstretch. The absorption of the polymer werecharacterized at 28, 60, and 90 days and showed a nearly completeabsorption at the final time point. The everolimus formulation evaluatedhad a D:P=1:3 using the PLLA-GACL 60/15/25 copolymer. FIG. 1 shows thatthe polymer mass was decreased by 80% within 60 days and that no polymerwas detected on the stent at the 3 month timepoint.

Studies on drug release profile of coatings formed of PDLA-GA-CL60/15/25 with various drug to polymer ratio formulations were performed.Table 1 summarizes drug release for PDLA-GA-CL (60/15/25) with variousD:P ratios after cold e-beam sterilization. The stents were formulatedfrom acetone/MIBK (90/10). The coating integrity after ebeamsterilization (1 pass, 25 kGy) showed smooth surface on both inner andouter surfaces (FIG. 3).

TABLE 1 Summary of Drug Release for PDLA-GA-CL (60/15/25) Total DrugContent RR day 1 RR day 3 Coating D:P Ratio Lot # (%) (%) (%) Integrity1:3 070507 83.5 ± 0.9 71.0 ± 5.5 93.4 ± 0.5 Pass 1:5 070507 83.0 ± 1.056.5 ± 2.2 86.6 ± 0.5 Pass 1:3 with 071807 84.3 ± 0.4 41.6 ± 2.6 77.4 ±2.9 Pass Topcoat Previous 060807 88.4 ± 0.4 66.7 ± 3.2 94.5 ± 0.7 Pass1:3 study

Table 2 summarizes the drug release profile for the PLLA -GA-CL 60115/25from various D:P ratios and lots.

Table 2 below shows the drug release profile for the PLLA-GA-CL 60/15/25from various D:P ratios and lots. After Ebeam sterilization, FIG. 3shows acceptable coating integrity, while FIG. 5 shows that after EtOsterilizaticn (40° C. cycle), slight to moderate polymer flow wasobserved on the ID of the stent. This flow is most probably due to thelow Tg of the terpolymer of <35° C.

TABLE 2 Drug Release for PLLA-GA-CL 60/15/25 with D:P = 1:3, EtOSolvent: Acetone/MIBK (90/10) 1 day RR 3 day RR Sample (EtO) TC (n = 3)(n = 3) (n = 3) D:P = 1:3 Lot 082807_A 91.9 ± 0.7 43.8 ± 3.7 61.8 ± 1.6D:P = 1:3 Lot 082807_B 91.4 ± 1.2 49.3 ± 0.8 66.2 ± 1.0 D:P = 1:3 Lot082807_S 91.4 ± 1.2 59.3 ± 0.6 78.4 ± 1.8 D:P = 1:4 Lot 082807_A 91.7 ±1.8 41.6 ± 5.4 61.8 ± 1.6 D:P = 1:4 Lot 082807_B 91.4 ± 1.2 49.3 ± 0.866.2 ± 2.0 D:P = 1:4 Lot 082807_S 91.4 ± 1.2 59.3 ± 0.6 78.4 ± 1.8

FIG. 4 shows after ebeam sterilization, the coatings formed of theterpolymer disclosed herein have satisfactory coating integrity.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the claims are to encompasswithin their scope all such changes and modifications as fall within thetrue sprit and scope of this invention.

1. An implantable device, comprising a coating comprising a layercomprising a terpolymer comprising caprolactone, glycolide and a thirdmonomer, which terpolymer has a molar composition where caprolactone isabout 20% or higher, and glycolide is about 10% or higher, wherein thecoating has a thickness of about 5 microns or less and a degradation orabsorption rate that within a period of 6 months after deployment of theimplantable device, the coating has a mass loss of about 80% or more. 2.The implantable device of claim 1, wherein the third monomer is lactide.3. The implantable device of claim 2, wherein the lactide is D,L-lactideor L-lactide.
 4. The implantable device of claim 1, therein theterpolymer has a glass transition temperature (T_(g)) less than 37° C.5. The implantable device of claim 3, therein the terpolymer has a T_(g)less than 37° C.
 6. The implantable device of claim 1, wherein thecoating further comprises a primer comprising a biodegradable amorphouspolymer.
 7. The implantable device of claim 3, wherein the coatingfurther comprises a primer comprising a biodegradable amorphous polymer.8. The implantable device of claim 1, wherein the coating furthercomprises a bioactive agent and provides a controlled release of thebioactive agent when the implantable device is deployed.
 9. Theimplantable device of claim 3, wherein the coating further comprises abioactive agent and provides a controlled release of the bioactive agentwhen the implantable device is deployed.
 10. The implantable device ofclaim 8, wherein the coating further comprises a bioactive agent in thelayer comprising the terpolymer and provides a controlled release of thebioactive agent when the implantable device is deployed.
 11. Theimplantable device of claim 1, wherein the coating a degradation orabsorption rate that within a period of about 100 days after deploymentof the implantable device, the coating has a mass loss of about 80% ormore.
 12. The implantable device of claim 1, which is a stent.
 13. Theimplantable device of claim 1, which is a bioabsorbable stent.
 14. Theimplantable device of claim 1, wherein the coating maintains itsintegrity after ethylene oxide (ETO) sterilization or e-beam treatment.15. The implantable device of claim 1, wherein the coating has a massloss of about 100% within 100 days or 180 days after deployment of theimplantable device.
 16. The implantable device of claim 8, wherein thebioactive agent is selected from paclitaxel, docetaxel, estradiol,17-beta-estradiol, nitric oxide donors, super oxide dismutases, superoxide dismutase mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), biolimus, tacrolimus, dexamethasone, dexamethasonederivatives, glucocorticoids, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), temsirolimus, deforolimus,γ-hiridun, clobetasol, pimecrolimus, imatinib mesylate, midostaurin,feno fibrate, prodrugs thereof, co-drugs thereof, and combinationsthereof.
 17. The implantable device of claim 8, wherein the bioactiveagent is selected from paclitaxel, docetaxel, estradiol,17-beta-estradiol, nitric oxide donors, super oxide dismutases, superoxide dismutase mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), biolimus, tacrolimus, dexamethasone, dexamethasonederivatives, glucocorticoids rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), temsirolimus, deforolimus,γ-hiridun, clobetasol, pimecrolimus, imatinib mesylate, midostaurin,feno fibrate, prodrugs thereof, co-drugs thereof, and combinationsthereof.
 18. A method of fabricating an implantable device, comprisingforming a coating comprising a layer comprising a terpolymer comprisingcaprolactone, glycolide and a third monomere, which terpolymer has amolar composition where caprolactone is about 20% or higher, andglycolide is about 10% or higher, wherein the coating has a thickness ofabout 5 microns or less and a degradation or absorption rate that withina period of 6 months after deployment of the implantable device, thecoating has a mass loss of about 80% or more.
 19. The method of claim18, wherein the third monomer is lactide.
 20. The method of claim 19,wherein the lactide is D,L-lactide or L-lactide.
 21. The method of claim20, therein the terpolymer has a glass transition temperature (T_(g))less than 37° C.
 22. The method of claim 18, wherein the coating furthercomprises a primer comprising a biodegradable amorphous polymer.
 23. Themethod of claim 20, wherein the coating further comprises a primercomprising a biodegradable amorphous polymer.
 24. The method of claim18, wherein the coating further comprises a bioactive agent and providesa controlled release of the bioactive agent when the implantable deviceis deployed.
 25. The method of claim 20, wherein the coating furthercomprises a bioactive agent and provides a controlled release of thebioactive agent when the implantable device is deployed.
 26. The methodof claim 18, wherein the coating a degradation or absorption rate thatwithin a period of about 100 days or 180 days after deployment of theimplantable device, the coating has a mass loss of about 80% or more.27. The method of claim 18, which is a stent.
 28. The method of claim18, which is a bioabsorbable stent.
 29. The method of claim 18, whereinthe coating maintains its integrity after ethylene oxide (ETO)sterilization or e-beam treatment.
 30. The method of claim 18, whereinthe coating has a mass loss of about 100% within 100 days or 180 daysafter deployment of the implantable device.
 31. A method of treating,preventing, or ameliorating a vascular medical condition, comprisingimplanting in a patient an implantable device according to claim 1,wherein the vascular medical condition is selected from restenosis,atherosclerosis, thrombosis, hemorrhage, vascular dissection orperforation, vascular aneurysm, vulnerable plaque, chronic totalocclusion, claudication, anastomotic proliferation (for vein andartificial grafts), bile duct obstruction, ureter obstruction, tumorobstruction, or combinations of these.